Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et al., 2011) of which 70% are able to adequately control their symptoms with the available existing anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie et al., 2012), are unable to obtain seizure freedom from the AED that are available and as such are termed as suffering from intractable or “treatment-resistant epilepsy” (TRE).
Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (I LAE) as “failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” (Kwan et al., 2009).
Individuals who develop epilepsy during the first few years of life are often difficult to treat and as such are often termed treatment-resistant. Children who undergo frequent seizures in childhood are often left with neurological damage which can cause cognitive, behavioral and motor delays.
Childhood epilepsy is a relatively common neurological disorder in children and young adults with a prevalence of approximately 700 per 100,000. This is twice the number of epileptic adults per population.
When a child or young adult presents with a seizure, investigations are normally undertaken in order to investigate the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations and as such diagnosis for these children may take some time.
The main symptom of epilepsy is repeated seizures. In order to determine the type of epilepsy or the epileptic syndrome that a patient is suffering from an investigation into the type of seizures that the patient is experiencing is undertaken. Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the ILEA classification described below and in FIG. 1.
The International classification of seizure types proposed by the ILAE was adopted in 1981 and a revised proposal was published by the ILAE in 2010 and has not yet superseded the 1981 classification. FIG. 1 is adapted from the 2010 proposal for revised terminology and includes the proposed changes to replace the terminology of partial with focal. In addition the term “simple partial seizure” has been replaced by the term “focal seizure where awareness/responsiveness is not impaired” and the term “complex partial seizure” has been replaced by the term “focal seizure where awareness/consciousness is impaired”.
From FIG. 1 it can be seen that Generalised seizures, where the seizure arises within and rapidly engages bilaterally distributed networks, can be split into six subtypes: Tonic-Clonic (grand mal) seizures; Absence (petit mal) Seizures; Clonic Seizures; Tonic Seizures; Atonic Seizures and Myoclonic Seizures.
Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories. Here the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness/responsiveness. Where a seizure begins as a localized seizure and rapidly evolves to be distributed within bilateral networks this seizure is known as a bilateral convulsive seizure, which is the proposed terminology to replace Secondary Generalized Seizures (generalized seizures that have evolved from focal seizures and are no longer remain localized).
Focal seizures where the subject's awareness/responsiveness is altered are referred to as focal seizures with impairment and focal seizures where the awareness or responsiveness of the subject is not impaired are referred to as focal seizures without impairment.
Aicardi Syndrome is caused by a genetic malformation which results in complete or partial absence of the corpus callosum in the brain. Children suffering from Aicardi syndrome often additionally present with retinal abnormalities. Seizures usually begin in infancy (infantile spasms), which tend to progress to recurrent seizures (epilepsy) that can be difficult to treat. The seizures associated with Aicardi Syndrome include focal seizures with impairment; infantile spasm; clonic seizures; tonic seizures; tonic-clonic seizures; atonic seizures; myoclonic seizures; absence seizures; and focal seizures evolving to secondary generalised seizures.
Epileptic syndromes such as Aicardi Syndrome often present with many different types of seizure. Identifying the types of seizure that a patient is suffering from is important as many of the standard AED's are targeted to treat a given seizure type these can be both generalised (particularly tonic) and partial seizure types.
Common AED defined by their mechanisms of action are described in the following tables:
TABLE 1Examples of narrow spectrum AEDNarrow-spectrumAEDMechanismIndicationPhenytoinSodium channelComplex partialTonic-clonicPhenobarbitalGABA/Calcium channelPartial seizuresTonic-clonicCarbamazepineSodium channelPartial seizuresTonic-clonicMixed seizuresOxcarbazepineSodium channelPartial seizuresTonic-clonicMixed seizuresGabapentinCalcium channelPartial seizuresMixed seizuresPregabalinCalcium channelAdjunct therapy for partialseizures with or withoutsecondary generalisationLacosamideSodium channelAdjunct therapy for partialseizuresVigabatrinGABASecondarily generalized tonic-clonic seizuresPartial seizuresInfantile spasms due to Westsyndrome
TABLE 2Examples of broad spectrum AEDBroad-spectrumAEDMechanismIndicationValproic acidGABA/Sodium channelFirst-line treatment for tonic-clonic seizures, absenceseizures and myoclonicseizuresSecond-line treatment forpartial seizures and infantilespasms.Intravenous use in statusepilepticusLamotrigineSodium channelPartial seizuresTonic-clonicSeizures associated withLennox-Gastaut syndromeTopiramateGABA/Sodium channelSeizures associated withLennox-Gastaut syndromeZonisamideGABA/Calcium/SodiumAdjunctive therapy in adultschannelwith partial-onset seizuresInfantile spasmMixed seizureLennox-Gastaut syndromeMyoclonicGeneralised tonic-clonicseizureLevetiracetamCalcium channelPartial seizuresAdjunctive therapy for partial,myoclonic and tonic-clonicseizuresClonazepamGABATypical and atypical absencesInfantile myoclonicMyoclonic seizuresAkinetic seizuresRufinamideSodium channelAdjunctive treatment ofpartial seizures associatedwith Lennox-Gastautsyndrome
TABLE 3Examples of AED used specifically in childhood epilepsyAEDMechanismIndicationClobazamGABAAdjunctive therapy in complexpartial seizuresStatus epilepticusMyoclonicMyoclonic-absentSimple partialComplex partialAbsence seizuresLennox-Gastaut syndromeStiripentolGABASevere myoclonic epilepsy ininfancy (Dravet syndrome)
Over the past forty years there have been a number of animal and human studies on the use of the non-psychoactive cannabinoid cannabidiol (CBD) to treat seizures.
A study in 1978 provided 200 mg/day of pure CBD to four adult patients, two of the four patients became seizure free, whereas in the remainder, seizure frequency was unchanged (Mechoulam and Carlini, 1978).
Cunha et al. reported that administration of CBD to eight adult patients with generalized epilepsy resulted in a marked reduction of seizures in 4 of the patients (Cunha et al., 1980) and Consroe et al., (1982) determined that CBD was able to prevent seizures in mice after administration of pro-convulsant drugs or an electric current.
In contrast to the studies described above, an open label study reported that 200 mg/day of pure CBD was ineffective in controlling seizures in twelve institutionalized adult patients (Ames and Cridland, 1986).
All of the studies described above focused on the treating subjects suffering from generalised epilepsy and did not look at the treatment of specific seizure sub-types.
More recently, WO 2011/001169 describes the use of CBD in the treatment of focal seizures, WO 2012/093255 describes the use of CBD in combination with standard anti-epileptic drugs in the treatment of epilepsy and WO 2013/045891 describes a composition comprising CBD and CBDV for use in the treatment of epilepsy.
In November 2013 the company GW Pharmaceuticals made a press release to state that they were intending to treat Dravet Syndrome with CBD as it had received orphan drug designation. The company made a further press release in February 2014 that that they were intending to treat Lennox-Gastaut Syndrome with CBD as it had also received orphan drug designation.
Again the rationale was to treat a disease as opposed to the type of seizure that the subject experienced.
It has additionally been suggested that cannabis which is enriched in CBD may be efficacious in the treatment of epilepsy. A case study of a child with Lennox-Gastaut syndrome showed improvement in seizure frequency after treatment with CBD in an oily solution was reported in 2005 (Pelliccia et al. 2005).
Porter and Jacobson (2013) report on a parent survey conducted via a Facebook group which explored the use of cannabis which was enriched with CBD in children with treatment-resistant epilepsy. It was found that sixteen of the 19 parents surveyed reported an improvement in their child's epilepsy. The children surveyed for this paper were all taking cannabis that was purported to contain CBD in a high concentration although the amount of CBD present and the other constituents including THC were not known for many of the cases. Indeed, whilst CBD levels ranged from 0.5 to 28.6 mg/kg/day (in those extracts tested), THC levels as high as 0.8 mg/kg/day were reported. Providing children with TRE with a cannabis extract that comprises THC, which has been described as a pro-convulsant (Consroe et al., 1977), at a potentially psychoactive dose of 0.8 mg/kg/day, is a concern.
In addition a paper published in June 2014 describes the use of a high-CBD strain to treat a patient with Dravet Syndrome; the patient's seizure frequency was stated to be reduced by the treatment (Maa et al. 2014).
A document published after the priority application was filed discloses the use of CBD in the treatment of refractory epilepsy in the treatment of Tuberous Sclerosis Complex in patients having focal onset seizures (Geffrey et al., 2014).
A number of websites have suggested that the use of CBD in the treatment of Aicardi Syndrome may be beneficial, including the Denver Post “Legalization's opening of medical pot research is dream and nightmare” and Salutaris Drops which include posts entitled “Cannabidiol for Aicardi Syndrome”. These documents describe the use of medical marijuana which has not undergone rigorous testing and cannot make any claims to efficacy.
Whilst the potential of cannabis and the cannabinoids, including CBD, to treat epilepsy has been rekindled, to date there has been little in the way of real data to support its efficacy in patients.
The applicant has found that CBD shows significant efficacy in patients with Aicardi Syndrome. These patients demonstrated a reduction in total seizures of 69%; and reduction in convulsive seizures of 77% and a reduction in a commonly occurring seizure type associated with Aicardi Syndrome, focal seizures with impairment of 62% and a reduction of infantile spasms of 55.5%.
It is additionally worth noting that the patients being treated were treatment resistant to existing AED and so consequently these figures are even the more remarkable.